Non‐antimicrobial, or “outside the box,” approaches to CDI treatment and prevention can be divided into 3 groups: intraluminal toxin binders or neutralizers, biotherapeutics to restore the protective microbiota, and antibodies (active and passive) to improve CDI immunity (Table 1). The attraction of these approaches is that they all avoid the continued suppression of normal bacterial microbiota that occurs with antimicrobial management.
Intraluminal toxin neutralization. Toxin‐binding agents, such as the anion‐exchange resins cholestyramine and colestipol, were initially thought to be beneficial in CDI management, but a placebo‐controlled clinical trial of colestipol showed no advantage over placebo, and in the hamster model, cholestyramine also proved ineffective. A toxin binder using oligosaccharide sequences to bind toxin A was attached to an inert support system (SYNSORB) and was evaluated in animals, with some success; it was also tried for patients, but the study never reached formal publication of results before being abandoned. Because there was no attempt to bind toxin B, it is not clear how successful this approach would have been. One toxin‐binding agent, the high molecular weight (>400 kDa) anionic polymer tolevamer, showed promise in hamster studies and in a phase 2 trial versus vancomycin. Toxin neutralization for a variety of C. difficile isolates, including BI/NAP1/027 epidemic strains, was demonstrated in vitro. Unfortunately, in 2 phase 3 trials, tolevamer was markedly inferior to both metronidazole and vancomycin in treatment response, although it did demonstrate a significantly decreased recurrence rate in patients who responded. It is unclear why tolevamer failed in these studies, but its in vitro affinity for toxin A was much higher than that for toxin B, and an essential role for toxin B in CDI pathogenesis has been reported. In the human gut model of CDI, tolevamer was not effective in neutralizing C. difficile toxins, consistent with the results of the phase 3 clinical trials.
Intraluminal toxin binding has also been attempted with antibodies to toxins A and B generated by vaccination of animals, harvesting of antibodies from milk or eggs, and oral administration of antibodies to treat or prevent CDI by neutralization of toxins in the gut lumen. Immunization of cows and chickens with toxin A and toxin B proteins has yielded antibodies in milk and eggs that, when administered orally to hamsters, protected against CDI. Bovine‐derived immunoglobulin G (IgG) has been found to be degraded by acid conditions and by transit through the human gastrointestinal tract; however, toxin neutralizing activity was detectable in human feces and ileal fluid. Successful human prevention and treatment trials of bovine‐ and chicken‐derived IgG antibodies have not been reported, possibly because of difficulty in delivering an effective neutralizing dose of IgG to the colon.